Abbreviations DC: dendritic cell; HSV: herpes simplex virus; LC: Langerhans cell.
Dendritic cells (DCs) are important in driving HIV/SIV dissemination, and sentinel immature DCs in peripheral tissue are front-line candidates. This is augmented by their specialized ability to communicate with lymphocytes, and to recognize and internalize pathogens. The latter has been attributed to the uptake of HIV/SIV by C-type lectin receptors such as CD209/DC-SIGN and CD206/mannose receptor [1•,2–4]. Several studies have concentrated on C-type lectin receptor-mediated virus capture by DCs and the subsequent transfer of virus to CD4 lymphocytes. However, the explosive viral replication observed in DC–CD4 T-cell co-cultures cannot be attributed to DC virus uptake and transfer alone. Rather, it is also dependent on the capacity of DCs to contact and stimulate CD4 T cells, and may also be dependent on infected immature DCs synthesizing new virions to spread to the T cells in a second round of transmission [1•,5].
Investigators have tracked the virus in vivo during the earliest stages of it entering the body in an attempt to understand the pathway taken by the virus to establish infection [6••,7••]. Such studies underscored the complex environment that the virus faces at the mucosal barrier. For successful persistent infection, the virus must overcome these challenges, and certain thresholds need to be met. The concept of virions being taken up by DCs independent of their infection and trafficked to the lymph node is supported by current in-vivo observations [7••], but the quantity and quality of the virus in that model may not be enough to kick-start en masse virus replication in the lymph node. Local sustained virus replication in mucosal resting and activated lymphocytes, resulting in unbroken chains of transmission, appears to be another predominant way to establish infection [6••,7••,8].
Notably, DCs and CD4 lymphocytes often exist within the same environment. DC–CD4 lymphocyte interactions within the mucosa and lymphoid tissues are probably essential in driving infection and amplification in resting T cells, as suggested by recent in-vivo observations [9,10]. Whether this involves DCs providing the necessary signals for infected resting T cells to replicate virus, or undetectably low levels of virus in the DCs being transmitted to the T cells for amplification [11–13], has yet to be determined. Moreover, HIV/SIV-induced modifications of DC biology, as well as changes effected by other co-pathogens [e.g. herpes simplex virus (HSV) type 2] can further alter this milieu to promote virus amplification instead of antiviral immunity.
Crossing the mucosal barrier to seed the early sites of infection
The contrasting effects of estrogen and progesterone on virus transmission have been known for some time [14,15]. Smith et al. [16•] recently proposed estrogen as a microbicide to protect against sexual transmission, because the thickening of the vaginal epithelium in response to the hormone coincided with protection against vaginal infection. Early visualization of virions coating the cervical epithelium 24 h after inoculation with SIVmac251 demonstrated the ability of the cervical mucosa to act almost like a ‘sponge’, with virus persisting on the epithelium, even though most of the virus had already been cleared from the cervicovaginal fluids [7••].
Post inoculation, infection was observed after 72 h in small clusters of cells within the cervicovaginal mucosa [7••]. Analysis of target cell availability and infection at the periphery revealed a predominance (92%) of resting CD4 lymphocytes being infected (CD3+CD4+Ki67− resting versus CD3+CD4+Ki67+ activated cells) [6••]. Although fewer in number, activated CD4 lymphocytes outranked their resting counterparts in virion production by 10-fold, as determined by examining in-situ cervicovaginal sections of exposed animals. Zhang and colleagues [6••] concluded that transmission occurs via the infection of resting CD4 lymphocytes on the basis of sheer availability, and that as infection persists, activated CD4 lymphocytes are recruited and subsequently take over the bulk of virion production. Given that activated lymphocytes can produce more virions, the distance and probability of infection of neighboring cell types increases, facilitating infection in distal lymphatic tissues. Infected DCs or macrophages were not observed and, therefore, were not included in the model. The reality may be that the availability of permissive cell types and mass production of virus is important, but the delivery of virus by sparsely infected/virus-carrying DCs or macrophages may indeed represent a ‘quality’ rather than ‘quantity’ mechanism (Fig. 1).
In the ‘quality’ rather than ‘quantity’ hypothesis, first we need to note that DCs need only be infected at extremely low levels to establish explosive viral replication in CD4 lymphocyte co-cultures [11–13]. Such low-level infection of (and possibly capture by) DCs can go undetected until DCs contact CD4 lymphocytes [11–13]. It is thus possible that this occurs in vivo, but that virus is not detected within the DCs/macrophages and only in the CD4 T cells once virus has been amplified sufficiently. Second, the migratory capacity of DCs  overcomes the need for them to produce virions to the extent of activated lymphocytes in order to disseminate virus over long distances. Third, the ability of DCs to contact numerous CD4 lymphocytes either in peripheral or lymphatic tissues during their lifespan of being infected further enhances their chances of spreading infectious virus. Finally, DCs efficiently deliver virus via a virological synapse to CD4 lymphocytes [1•,18,19,20•]. These are all characteristics of DCs doing a lot with very little (see Fig. 1 for a contrasting look at the en masse T-cell versus DC-mediated transmission hypotheses). Adding to this, DCs would also probably be recruited to the initial sites of infection along with activated T cells, to encourage DC–T-cell interactions further to promote HIV replication in the T cells.
Whether through DC-catalysed events or through sheer numbers, resting CD4 lymphocytes do appear to be the first line of HIV assault on the peripheral immune system. The early events of HIV and SIV transmission take a heavy toll on the resting CD4 T-cell population and this is seen dramatically with significant drops in CD4 T cells within the lamina propria after only 6 days post-SIV vaginal challenge [21••]. Of interest is that the resting CD4 phenotype is defined as CD45RO memory [21••,22••], and depletion is correlated with infection, given that 90% of the infected cells in the lamina propria are memory T cells [21••]. Predominant infection and loss of memory CD4 lymphocytes supports the en masse hypothesis to some degree (Fig. 1 upper panel). Although the loss in numbers is astounding, and other mechanisms that increase the efficiency of such CD4 T cells would also be supported. Earlier work showed that resting memory CD4 T cells conjugated to DCs create an explosive site for virus replication . With respect to DCs, recent work using skin explants has demonstrated that Langerhans cells (LCs) preferentially conjugate with CD4 lymphocytes of memory phenotype, and more importantly, when LCs are previously exposed to HIV, they have a greater capacity to transfer and drive viral replication [23••]. LCs or other circulating DCs that are either infected or are carrying virus thus have the capacity to home in on the memory CD4 cells, infect them, stay conjugated for T-cell activation and thus further exacerbate the situation. In addition, virus taken up and processed by DCs for CD4 lymphocyte recognition may have the undesired impact of infecting and recruiting HIV-specific CD4 lymphocytes .
Distinct contributions of dendritic cell subsets
In a study using macaques [7••], an intriguing observation was the evidence of rapid viral dissemination into lymphatic tissues 1–3 days after cervicovaginal exposure in half of the animals. In one animal exposed to non-infectious SIV, virus was detected in the axillary lymph node within 24 h. The speed with which this occurs was attributed to DCs, because LCs traffic HIV in mice with similar kinetics . Indirect observations of cells trafficking SIV to the subcapsular sinuses also implicate LCs or lamina propria DCs in the rapid trafficking of virus in macaques [26••,27]. Despite this, Miller et al. [7••] reported that productive infection as a result of such dissemination to the lymphatic tissue does not appear until 5–6 days post-exposure. The authors concluded that this is consistent with a model of early viral seeding within mucosal T cells that must reach a significant magnitude or threshold level sufficient then to seed the lymphatic tissue. Another interpretation of this is that DCs traffic quickly to the lymph nodes, but viral replication in DCs is somewhat delayed compared with that in lymphocytes, thus accounting for this time lag. In-vitro studies have shown that the ability of immature DCs to transmit newly produced viruses to T cells typically peaks 72–96 h after the initial DC infection [1•] (Wilkinson et al., personal communication). Infected DCs at distal lymphatics would thus not start transmitting newly synthesized virus to CD4 lymphocytes until at least 72 h later. This is supported in recent studies by Wang et al. [26••], in which infected cells were detected in the axillary lymph nodes 16 h post-exposure, but only when further culturing isolated samples for at least 6 days in vitro.
Although the DCs of the cervicovaginal tissues have received much attention with respect to virus transmission, other DC subsets located in different mucosal tissues that may also be exposed to virus (e.g. rectal, oral), need to be addressed. Gurney et al. [28••] reported significant levels of CD209-positive cells within the rectal mucosa. As in previous studies , the majority of these cells were CD14-positive and it is unclear what proportion were DCs or macrophages. Curiously, these cells do not express detectable CCR5 or CXCR4. Therefore, the capacity of these cells to be infected appears to be low. CD209-positive cells extracted from tissue bound virus to a greater extent than CD209-negative HLA-DR-positive cells, and this correlated with their ability to transfer virus to activated CD4 lymphocytes.
It is important to note that CD209−HLA-DR+ cells still retain the capacity to transfer significant levels of virus. This is supported by studies by Lore et al. , which showed that circulating DCs with low to undetectable levels of CD209 (like those found in the lymphoid follicles associated with the mucosal tissues) also transfer virus to CD4 lymphocytes in the short term. This highlights the fact that within a DC background several other mechanisms are at play that are independent of CD209. The study by Gurney et al. [28••] is also intriguing with respect to the sheer abundance of CD209 expression that they reported in the rectal mucosa. If the initial hypothesis of CD209 binding, uptake, and long-term carriage of virus to the lymph nodes were entirely true, then why is the incidence of transmission so low? The fact that these subsets do not express detectable levels of CXCR4 or CCR5 may render such cells less capable of the long-term carriage of virus given that they cannot be infected. One may, however, argue that the DCs need not be infected in order to transfer virus in the long term.
The recent reports on the long-term carriage in DCs or CD209-expressing cells have yielded conflicting results. Recent studies have supported previous findings that infectious virus transfer from DCs to CD4 lymphocytes in the long term is dependent on DC infection [30•]. Lore and colleagues  also undertook the arduous task of examining blood DCs, to show that infection of both myeloid and plasmacytoid DCs is a prerequisite for long-term viral transfer to responding CD4 lymphocytes. However, other work supports the notion that in the absence of DC infection, virus persisting in CD81-positive intracellular compartments can be later transferred to an infectious viral synapse [20•,31]. In contrast, when others addressed infection in the DCs, through the use of antiretroviral inhibitors or X4 HIV isolates that do not infect DCs well, there was lack of evidence for a significant contribution from the initial viral inoculum in later transfer events [1•,12,29,30].
The importance of infection at the mucosa
Animal transmission studies support the existence of several mechanisms of virus transmission: CD4 T-cell infection at the mucosa, as well as early virus trafficking via DCs. Microbicide studies have inadvertently highlighted that infection at the periphery is important [32,33••]. The specific inhibition of CCR5 with compounds PSC–regulated upon activation: normal T-cell expressed/secreted or CMPD167 applied to the mucosa protected macaques against vaginal challenge with SHIV 162P3 [32,33••].
This supports findings using mucosal explant tissues, in which the application of virus to the tissue surface resulted in infection of mucosal cells, which could be blocked by CCR5 inhibitors . This might reflect the direct inhibition of the infection of permissive CD4 lymphocytes, as well as immature DCs or macrophages, but also the subsequent local CCR5-dependent spread of virus from DCs to CD4 lymphocytes. The levels of CXCR4 and CCR5 expression within mucosal sites may not (alone) explain the selective infection with CCR5 . Moreover, SIV and HIV-2 (not HIV-1) nef-mediated downregulation of CXCR4 could interfere with the CXCR4-mediated migration of cells, exacerbating virus spread or impairing immunity .
Dendritic cell-driven immune responses during transmission
Whereas DCs can rapidly promote virus infection, their true role is to orchestrate innate and adaptive immunity [36,37]. As noted earlier, the epithelia constitutes a physical barrier to infection, but in addition, antimicrobial products (i.e. defensins)  and innate and adaptive mechanisms, mounted by mucosal sentinel cells, play an important role . DCs are particularly important in the mucosal immune responses because they are among the first cells to encounter a pathogen and they have the unique ability to induce the stimulation of naive T cells . DCs respond to microbial stimuli, undergoing a process of phenotypic and functional maturation necessary for antigen processing, presentation and migration to lymphoid organs. Different pathogens, including HIV, subvert the role of DCs, thereby evading the host immune responses [36,39]. How this might influence the early stages of infection must be contemplated.
HIV infection of DCs can prevent their full maturation, thus reducing their ability to secrete IL-12 and stimulate effective T-cell responses [40••,41]. Partial DC maturation upon exposure to HIV  or SIV  has also been observed in the circulating DC subsets. Adding to previous findings, viral determinants have been shown to alter the maturation responses of DCs, rendering them unable to perform their normal potent immunostimulatory functions [44•,45,46]. The early innate IFN-α responses of DCs to HIV/SIV might help control the initial expansion of virus in the tissues [42,43,46]. However, the limited IL-12 production and suboptimal co-stimulatory molecule expression by virus-exposed DCs probably contributes to the activation of mediocre adaptive immunity that is incapable of clearing infection.
The evasion of DC-driven immune responses is further aggravated by co-pathogens that target mucosal tissues. Sexually transmitted diseases can increase the acquisition and transmission of HIV-1 at the mucosa. This occurs through different mechanisms, including disruption of the mechanical barriers, an increase in the inflammatory cytokines and chemokines resulting in the recruitment of HIV-permissive target cells to the site, and the impairment of the innate (and ultimately adaptive) immune responses at the site of the infection .
Genital herpes is one of the most common causes of sexually transmitted diseases and genital ulcers. Individuals with HSV-2 infection exhibit an increased risk of HIV acquisition [47–49], especially during periods of HSV-2 reactivation . In addition to HSV-2-induced ulcerative lesions, HSV and HIV can also co-infect lymphocytes and some HSV regulatory proteins can transactivate the HIV replication interacting with the HIV promoter . Antiviral treatment of HSV-2 infection as well as prophylactic vaccines or topical microbicides to prevent both HSV/HIV transmission should thus be evaluated as strategies to reduce HIV transmission [51–54].
Although the main targets of HSV-2 are epithelial cells and neurons, DCs play a central role in the innate and adaptive immune responses towards HSV-2. DCs encounter the virus at the onset of the infection in the sub and intra-epithelial compartments of the mucosa . Uninfected bystander non-epidermal DCs can phagocytose HSV-infected apoptotic DCs and stimulate HSV-specific T-cell responses [56•], probably contributing to antiviral responses that help clear lesions. However, HSV-2 infection of DCs compromises their immunostimulatory functions [56•,57,58•], by downregulating several co-stimulatory molecules needed for the induction of potent T-cell responses and by stimulating the release of cytokines such as IL-6, which can prevent DC maturation [58•]. The overall effect is the activation of anti-HSV-2 immunity that is only sufficient to curb virus reactivation, but not to clear or prevent infection. Of note is the fact that HSV-2-infected macaque DCs are impaired in their ability to stimulate SIV-specific T cells [58•]. This represents the first evidence that HSV-2-infected DCs can be compromised in inducing a prompt and effective SIV-specific response, and has important implications in HIV/SIV transmission. These observations support the notion that, in addition to DCs driving infection, DC-orchestrated early innate and ultimately adaptive responses to HIV influence the onset and spread of infection.
The complex biology of DCs and the unique ways HIV exploits them underlie the defining events during the earliest moments of HIV infection. Efficiently entrapping small amounts of infectious virus that are amplified in DCs or more permissive lymphocytes involves multiple cell surface molecules and the dampening of DC function. These multifaceted events will probably all need to be targeted to prevent HIV spread effectively.
The authors wish to thank Evan Read for his help with the original version of the graphics. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of the US Agency for International Development.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 91–92).
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